Quantitative assessment of the effects of a fixed 50% coronary artery stenosis on regional myocardial flow reserve and transmural distribution of blood flow

Experimental coronary artery stenoses produced by external constrictors that reduce vessel diameter by 50% under basal conditions have been shown to reduce myocardial hyperemic flow reserve. Because such lesions may exhibit dynamic increases in severity during coronary vasodilation, the results of these studies are not necessarily applicable to human patients with fixed, proximal coronary stenoses of similar baseline severity. Accordingly, the present study was conducted in 16 closed chest conscious pigs in order to assess the effects of a fixed, rigid 50% stenosis on maximal myocardial hyperemic flow and transmural distribution of blood flow. Eight pigs (Group I, stenosis) were instrumented with a 50% stenosis and eight were not (Group II, control). After obtaining control measurements of hemodynamics and regional myocardial blood flow (microsphere technique), adenosine was infused at doses of 100, 200 and 400 μg min-1(x 10 minutes at each dose) directly into the left anterior descending coronary bed distal to the stenosis (Group I) or at a similar level in animals without a stenosis. Hemodynamics and blood flow measurements were made at the 10th minute of each infusion level of adenosine.The results (mean ± 1 standard deviation) of the study were as follows. Under basal conditions, transmural, endocardial and epicardial flows (ml min-1g-1) in Group I pigs (1.48 ± 0.40, 1.51 ± 0.45 and 1.30 ± 0.35, respectively) did not differ significantly from respective flows in Group II pigs (1.56 ± 0.26, 1.57 ± 0.27 and 1.43 ± 0.30). Likewise baseline endocardial to epicardial flow ratios were comparable between the two groups (Group I = 1.16 ± 0.22 versus Group II =1.11 ± 0.09, p = NS). Transmural, endocardial and epicardial blood flow in Group I pigs increased to the same extent as respective flows in Group II pigs at each dose of adenosine tested. Maximal transmural, endocardial and epicardial flows in Group I pigs increased, respectively, to levels 3.56 ± 1.56, 3.56 ± 2.03 and 3.26 ± 1.16 above baseline values. Similar responses occurred in Group II (3.38 ± 1.02, 3.21 ± 0.91 and 3.25 ± 1.44, respectively). The endocardial/epicardial flow ratio in Group I at maximal vasodilation (1.20 ± 0.34) did not differ significantly from that in Group II (1.19 ± 0.34). Thus, the data demonstrate that in contrast to 50% stenoses formed with external coronary constrictors, fixed proximal 50% stenoses do not reduce maximal myocardial hyperemic flow reserve

S100A1: A Regulator of Striated Muscle Sarcoplasmic Reticulum Ca2+ Handling, Sarcomeric, and Mitochondrial Function

Calcium (Ca2+) signaling plays a key role in a wide range of physiological functions including control of cardiac and skeletal muscle performance. To assure a precise coordination of both temporally and spatially transduction of intracellular Ca2+ oscillations to downstream signaling networks and target operations, Ca2+ cycling regulation in muscle tissue is conducted by a plethora of diverse molecules. Ca2+ S100A1 is a member of the Ca2+-binding S100 protein family and represents the most abundant S100 isoform in cardiac and skeletal muscle. Early studies revealed distinct expression patterns of S100A1 in healthy and diseased cardiac tissue from animal models and humans. Further elaborate investigations uncovered S100A1 protein as a basic requirement for striated muscle Ca2+ handling integrity. S100A1 is a critical regulator of cardiomyocyte Ca2+ cycling and contractile performance. S100A1-mediated inotropy unfolds independent and on top of βAR-stimulated contractility with unchanged βAR downstream signaling. S100A1 has further been detected at different sites within the cardiac sarcomere indicating potential roles in myofilament function. More recently, a study reported a mitochondrial location of S100A1 in cardiomyocytes. Additionally, normalizing the level of S100A1 protein by means of viral cardiac gene transfer in animal heart failure models resulted in a disrupted progression towards cardiac failure and enhanced survival. This brief review is confined to the physiological and pathophysiological relevance of S100A1 in cardiac and skeletal muscle Ca2+ handling with a particular focus on its potential as a molecular target for future therapeutic interventions

Don’t call me in the morning: why it might be best to see patients in-person, a case report

Case Diagnosis: Post-irradiation Sarcoma Case Description: A 58-year-old woman with a history of stage IIIB squamous cell carcinoma of the cervix who was treated with chemoradiation, considered in remission 5 years prior on PET CT, and was under every 6-months surveillance for recurrence by gynecology. She presented to the Emergency Department for severe back pain, left sided sciatica, and paresthesias. In the absence of fracture or cord compression, she was discharged with recommendations for primary care follow-up. This took place over the telephone with referral to the spine center. One week later, her pain progressed to 10+/10 with dense left leg numbness, and multiple falls. Physiatry ordered a lumbar MRI for focal neurologic findings on exam, which revealed a large destructive lesion of the left ilium and left hemisacrum with soft tissue extension. This was later determined to be undifferentiated sarcoma, likely due to prior radiation. She is currently undergoing palliative chemotherapy. Discussions: Post-irradiation sarcomas (PIS) are a relatively rare event and exhibit dose dependency. Sarcomas can present with bone pain that can be worse at night and signs and symptoms of compression of surrounding structures. The pelvis is a common site for sarcoma development. Cases of PIS have presented in even just a few months post radiation therapy. The prognosis of patients with PIS is poorer than those with primary sarcomas. This patient would require hemipelvectomy to attempt curative treatment. Conclusions: PIS are typically aggressive, have poor prognosis, and can develop within months of high doses of radiation therapies; clinicians index of suspicion for sarcomas in patients with a history of radiation must be high. Evaluation for progressive pain, weakness, and numbness may not be amenable to telemedicine until technology improves. Patients that present with signs and symptoms of progressive nerve compression and bone pain should be re-examined early on

Total Joint Replacement Prehabilitation: A Feasibility Study

Objectives: Pre-operative physical therapy has been shown to reduce post-acute care service utilization. Shifting rehabilitation to the presurgical period, referred to as prehabilitation, could result in reduced recovery time and cost. Limited access to physical therapy may prevent patients from achieving the benefits, and a standard set of independent exercises may be an alternative. We aim to assess the feasibility of an independent exercise program as a pre-surgical intervention for total hip and knee replacement. Design: Participants were taught two exercises for hip or knee arthritis at least one week prior to surgery and instructed to perform them independently at home. Subjects were contacted three days to one month post-operatively and surveyed about discharge, frequency of exercise, and living status of alone or with others. No adverse effects were reported. Additional information was collected from the subjects’chart including age, BMI, and sex. Discharge outcomes were compared with pre-existing independent factors using univariate and multivariate analyses. Results: A total of 80 subjects were followed with a home discharge rate of 78.75%. Univariate analyses showed that the presence of other people in the home showed a slight, but non-significant, association with differences of discharge destination. 82.1%-83.3% of patients who live with others were discharged home versus 57.1% of patients living alone (LR chi-square: 3.84, p=0.15). Multivariate analyses showed a slight, but non-significant, association between frequency of prehabilitation and discharge destination (OR=1.212; 95% CI, 0.960-1.530). BMI showed no associated difference in discharge destination. Conclusions: Increased frequency of prehabilitation and presence of others at home showed slight associations with increased discharges to home, but were non-significant. Increased exposure to prehabilitation (duration times frequency) trends toward more frequent home discharge. Independently performed prehabilitation may be offered as an alternative pre-surgical intervention with likely little to no adverse effect. Larger numbers are needed to determine likelihood of discharge home

Emotion Modulation of Visual Attention: Categorical and Temporal Characteristics

Background: Experimental research has shown that emotional stimuli can either enhance or impair attentional performance. However, the relative effects of specific emotional stimuli and the specific time course of these differential effects are unclear. Methodology/Principal Findings: In the present study, participants (n = 50) searched for a single target within a rapid serial visual presentation of images. Irrelevant fear, disgust, erotic or neutral images preceded the target by two, four, six, or eight items. At lag 2, erotic images induced the greatest deficits in subsequent target processing compared to other images, consistent with a large emotional attentional blink. Fear and disgust images also produced a larger attentional blinks at lag 2 than neutral images. Erotic, fear, and disgust images continued to induce greater deficits than neutral images at lag 4 and 6. However, target processing deficits induced by erotic, fear, and disgust images at intermediate lags (lag 4 and 6) did not consistently differ from each other. In contrast to performance at lag 2, 4, and 6, enhancement in target processing for emotional stimuli was observed in comparison to neutral stimuli at lag 8. Conclusions/Significance: These findings suggest that task-irrelevant emotion information, particularly erotica, impairs intentional allocation of attention at early temporal stages, but at later temporal stages, emotional stimuli can have an enhancing effect on directed attention. These data suggest that the effects of emotional stimuli on attention can be bot

Spatiotemporal competition and task-relevance shape the spatial distribution of emotional interference during rapid visual processing:Evidence from gaze-contingent eye-tracking

People’s ability to perceive rapidly presented targets can be disrupted both by voluntary encoding of a preceding target and by spontaneous attention to salient distractors. Distinctions between these sources of interference can be found when people search for a target in multiple rapid streams instead of a single stream: voluntary encoding of a preceding target often elicits subsequent perceptual lapses across the visual field, whereas spontaneous attention to emotionally salient distractors appears to elicit a spatially localized lapse, giving rise to a theoretical account suggesting that emotional distractors and subsequent targets compete spatiotemporally during rapid serial visual processing. We used gaze-contingent eye-tracking to probe the roles of spatiotemporal competition and memory encoding on the spatial distribution of interference caused by emotional distractors, while also ruling out the role of eye-gaze in driving differences in spatial distribution. Spontaneous target perception impairments caused by emotional distractors were localized to the distractor location regardless of where participants fixated. But when emotional distractors were task-relevant, perceptual lapses occurred across both streams while remaining strongest at the distractor location. These results suggest that spatiotemporal competition and memory encoding reflect a dual-route impact of emotional stimuli on target perception during rapid visual processing

Bioinformatics and the politics of innovation in the life sciences: Science and the state in the United Kingdom, China, and India

The governments of China, India, and the United Kingdom are unanimous in their belief that bioinformatics should supply the link between basic life sciences research and its translation into health benefits for the population and the economy. Yet at the same time, as ambitious states vying for position in the future global bioeconomy they differ considerably in the strategies adopted in pursuit of this goal. At the heart of these differences lies the interaction between epistemic change within the scientific community itself and the apparatus of the state. Drawing on desk-based research and thirty-two interviews with scientists and policy makers in the three countries, this article analyzes the politics that shape this interaction. From this analysis emerges an understanding of the variable capacities of different kinds of states and political systems to work with science in harnessing the potential of new epistemic territories in global life sciences innovation

The M81 Group Dwarf Irregular Galaxy DDO 165. I. High Velocity Neutral Gas in a Post-Starburst System

We present new multi-configuration VLA HI spectral line observations of the M81 group dIrr post-starburst galaxy DDO 165. The HI morphology is complex, with multiple column density peaks surrounding a large region of very low HI surface density that is offset from the center of the stellar distribution. The bulk of the neutral gas is associated with the southern section of the galaxy; a secondary peak in the north contains ~15% of the total HI mass. These components appear to be kinematically distinct, suggesting that either tidal processes or large-scale blowout have recently shaped the ISM of DDO 165. Using spatially-resolved position-velocity maps, we find multiple localized high-velocity gas features. Cross-correlating with radius-velocity analyses, we identify eight shell/hole structures in the ISM with a range of sizes (~400-900 pc) and expansion velocities (~7-11 km/s). These structures are compared with narrow- and broad-band imaging from KPNO and HST. Using the latter data, recent works have shown that DDO 165's previous "burst" phase was extended temporally (>1 Gyr). We thus interpret the high-velocity gas features, HI holes, and kinematically distinct components of the galaxy in the context of the immediate effects of "feedback" from recent star formation. In addition to creating HI holes and shells, extended star formation events are capable of creating localized high velocity motion of the surrounding interstellar material. A companion paper connects the energetics from the HI and HST data.Comment: The Astrophysical Journal, in press. Full-resolution version available on request from the first autho

S100A1: A Multifaceted Therapeutic Target in Cardiovascular Disease

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca2+ binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca2+ handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists